Viral infection treatment with 5-aminolevulinic acid

ABSTRACT

A method for amelioriation of, or prophylaxis against, a viral infection comprising administering to a patient in need of treatment a therapeutically effective amount of 5 aminolevulinic acid, optionally with at least one of cucumarin nano, zinc, vitamin C and methylene blue, and compositions thereof. Such compositions may be used for the treatment of coronavirus infections, including the SARS-CoV-2 virus, and/or rhinoviruses.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to Indian Application Nos.2020/41017237, filed Apr. 22, 2020, and 2020/41026186, filed Jun. 4,2020, and is a divisional of U.S. patent application Ser. No.17/132,602, filed Dec. 23, 2020, now U.S. Pat. No. 11,026,909, which isa divisional of U.S. application Ser. No. 16/920,000, filed Jul. 2,2020, now U.S. Pat. No. 10,987,329.

TECHNICAL FIELD

The present invention relates to a method of treating viral infectionsin a subject in need thereof by administration, simultaneously orsequentially, of a therapeutically effective amount of 5-aminolevulinicacid with of at least one selected from the group of: an antioxidant,curcumin, zinc, and methylene blue. More particularly the presentinvention relates to a therapeutically effective combination of5-aminolevulinic acid and curcumin, combination of 5-aminolevulinic acidand zinc, a combination of 5-aminolevulinic acid, curcumin and vitaminC, and a combination of 5-aminolevulinic acid, zinc and curcumin in thetreatment of coronavirus infections. In another embodiment there isincluded a prescription formulation of 5-aminolevulinic acid andmethylene blue and other such combinations in conjunction with atherapeutically effective dose of methylene blue directed to COVID-19.Such combinations are used for the treatment (including amelioration andprotection) of coronaviruses infection, including Covid-19 infection,and common cold rhinoviruses.

BACKGROUND

Coronaviruses (CoV) are widespread viruses that cause a variety ofillnesses ranging from the common cold to COVID-19. Human rhinoviruses(HRV) are a large family of viruses causing many common viral infectionsin humans. It is believed that both coronaviruses and rhinoviruses havethe primary route of entry into humans via the upper respiratory tract,particularly the nose and mouth. Both coronaviruses and rhinoviruses areRNA viruses that cause disease in mammals. Rhinoviruses arenon-enveloped single stranded RNA virus, and a member of the Piconavirusfamily. Rhinoviruses have a substantially spherical surface interruptedby protein spikes often referenced as fingers. Coronaviruses arelipid-bilayer enveloped positive-sense, single-stranded RNA virus, and amember of the Coronaviridae family. Coronaviruses have club-shapedspikes that project from their substantial spherical surface. Bothcoronaviruses (particularly, HCoV-OC43, HCoV-HKU1, HCoV-229E, andHCoV-NL63) and rhinoviruses (particularly, rhinovirus A, B and C) arecausative agents of what is known as the common cold. Together theseviruses are thought as accounting for up to 65% of all common colds.Respiratory syncytial virus (“RSV”) and parinfluenza viruses are alsobelieved to cause the common cold. Other viruses are also likelyinvolved.

A new coronavirus, designated SARS-CoV-2, has ravaged the world since2019. This virus first jumped into humans in Wahun, Hubei Province,China, and then quickly spread across the world. The SARS-CoV-2 virushas been associated with numerous maladies including some seen withcommon cold infections such as cough, sore throat, fever or chills,fatigue, headache, muscle or body aches, nausea, diarrhea, andcongestion or runny nose. Other symptoms are largely distinct from thecommon cold, including shortness of breath, loss of taste or smell, andvomiting. The common cold also has been associated with sneezing whichhas not been reported as a common symptom of SARS-CoV-2 virus infection.In a pre-publication preprint by Nelde et al., SArS-CoV-2 T-cellepitopes define heterologous and COVID-19-induced T-cell recognition,Researchsquare.com, Jun. 17, 2020, the authors note that there issignificant sequence alignment seen in SARS-CoV-2 derived peptidesequences and that of seasonal common cold human coronaviruses(HCoV-OC43, HCoV-229E, HCoV-N163, HCoV-HKU1). These authors suggest thatheterologous immunity is seen between the common cold coronaviruses andSARS-CoV2. The group notes that cross-reactive SARS-CoV-2 T-cellepitopes revealed preexisting T-cell responses in 81% of personsunexposed to SARS-CoV-2.

COVID-19 represents a global public health concern and WHO has declaredit a public health emergency. SARS-CoV-2 rapidly increased in spread inan epidemic scale since its first appearance in Wuhan, China, aroundDecember 2019. Among the most alarming symptoms that may be associatedwith SARS-CoV-2 infection is severe acute respiratory syndrome seen in asubpopulation, particularly those over 60 years of age and thosesuffering from underlying conditions such as Type II diabetes, chronickidney disease, chronic obstructive pulmonary disease,immunocompromisation, a BMI of 30 or higher, heart conditions such asheart failure or coronary heart disease, and sickle cell disease. Thisrespiratory syndrome is also referenced as “Novel coronavirus-inducedpneumonia.” Besides respiratory issues, it has been found thatSARS-CoV-2 infection is associated with other serious life-threateningsequelae including blood clotting disorders that can lead to strokes,and with extreme inflammation that can lead to effects on multiple organsystems including the liver, the brain, and the kidney. The World HealthOrganization (“WHO”) on Feb. 11, 2020 designated the disease caused bySARS-CoV-2 as Coronavirus Disease 2019 (2019nCoV or COVID-19).Unfortunately, it now appears that many persons who suffer fromCOVID-19, and yet survive, may face many years of medical care due tothe damage caused by the virus. It is believed that nearly 50% ofhospitalized patients recovering from COVID-19 complain of debilitatingsyndromes weeks after recovering from the virus, such as pains in thearms and legs, shortness of breath, being unable to sleep, and severelethargy and anxiety.

SARS-CoV-2 has not less than ten open reading frames (ORFs). A majorportion of this RNA (also forms ORF1a/b) is translated into two largepolyproteins—pp1a and pp1ab, which are processed into 16 non-structuralproteins (nsp1-nsp16), which form the viral replicas transcriptasecomplex that helps viral replication and transcription in the roughendoplasmic reticulum (“RER”). The remaining RNA (other ORFs) encodefour main structural proteins: spike (S), envelope (E), nucleocapsid (N)and membrane (M) proteins, as well as several accessory proteins withunknown functions which are deemed to not participate in viralreplication.

The current theory suggests that the novel coronavirus binds to thehuman ACE2 receptor through a spike protein and subsequent phagocytosis.While this remain the predominant theory, some data suggests that thecoronavirus may also directly penetrate the human cell membrane by wayof porphyrin. The present inventors have hypothesized that no one singlemechanism of action is in play in regard to the detrimental effects ofany coronavirus, and in particular with regard to SARS-CoV-2, and thatto treat (by which it is meant proactively and preventively) the diseaseeffectively, multiple therapeutic interventions should be undertaken tothwart the virus.

Once the virus infects—it gets recognized by antigen presentation cells(APC) and then recognized by virus-specific cytotoxic T lymphocytes(CTLs). However the reaction of innate immunity to this virus is quitevaried. Besides HLA polymorphisms, gene polymorphisms of MBL(mannose-binding lectin) associated with antigen presentation arerelated to the risk of SARS-CoV-2 infection, which provide valuableclues for the prevention, treatment, and mechanism of COVID-19. Once theprocess of inflammation sets in and goes out of control “referred ascytokine storms” it leads to lung damage and ARDS—which is believed tobe the main death cause of COVID-19. Immune effector cells during thecytokine storm release large amounts of pro-inflammatory cytokines(IFN-α, IFN-γ, IL-1β, IL-6, IL-12, IL-18, IL-33, TNF-α, TGFβ, etc.) andchemokines (CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10, etc.).

Initial efforts to treat SARS-CoV-2 infection were directed to reduceRNAemia (viral load reduction) using broad-spectrum antiviral drugs likenucleoside analogues and HIV-protease inhibitors. Unfortunately, these(such as lopinavir-ritonavir) were not found to be very effective.Subsequently, pharmaceutical products, such as remdesivir, favipiravir,ribavirin and galidesivir), have been, or are still being, tested todetermine if they were capable of interfering with the immune evasion ofSARS-CoV-2. In particular, drugs thought capable of blocking the bindingof S protein with ACE-2 were investigated as possibly useful in thetreatment of COVID-19.

While vaccines and monoclonal antibodies are thought to be the long termsolution for COVID-19, given the wide global spread of SARS-CoV-2, andthe uncertainty as to the length of time any immunity by vaccination maylast, further research into treatment is needed. Similarly, thereremains a need for the treatment of other coronaviruses, in particularthose associated with the common cold.

In a study employing conserved domain analysis, homology modeling, andmolecular docking employing NCBI protein sequences it is found that ORF8and surface glycoprotein could bind to porphyrin, respectively. At thesame time, orf1ab, ORF10, and ORF3a proteins are seen to be able tocoordinate to attack the heme on the 1-beta chain of hemoglobin todissociate the iron to form porphyrin. Such a mechanism could be deemedto interfere with the normal heme anabolic pathway. In any case, suchstudy suggests that there is a massive demand of porphyrins for virusesto survive. Therefore, the novel coronavirus is hypothesized to targethemoglobin and attack heme. It may be that SARS-CoV-2 virus directlyinterferes with the assembly of human hemoglobin.

Protoporphyrin IX has been suggested in vitro to show antiviralactivities against a array of enveloped pathogenic viruses includingSARS-CoV-2 (Lu et al. Broad-spectrum antivirals of protoporphyrinsinhibt the entry of highly pathogenic emerging viruses, Pre-printbioRxiv May 9, 2020). Mice in vivo studies may suggest that with respectto certain viruses (but not Sars-CoV-2) that mean survival time and ratemay be improved. Id. It has been advanced that proporphyrin IX inhibitsinfection in the early stage of virus entry through biophysicallyinteracting with the hydrophobic lipids of enveloped virons, interferingwith the formation of a negative curvature for fusion, and resulting inthe blockage of the entry of enveloped viruses into host cells. Id.Studies before the rise of SARS-CoV-2 suggested porphyrins might beuseful for the inactivation of viruses including those of thecoronavirus varieties leading to the common cold.

5-ALA is known to be metabolized to protoporphyrin IX under certainconditions particularly in cancer cells. However, the rate of suchmetabolism from an exogenous source is not clear. It was thereforeunknown to the present inventors as to whether 5-ALA could produceenough protoporphyrin IX to aid in the treatment of coronavirusinfections, including that of the common cold and COVID-19. Certainly itwas unclear in respect of COVID-19 whether 5-ALA could aid in theinactivation of the virus or reduce coagulation disorders given the needof metabolism.

The inventors realized that porphyrin is an important material for thesynthesis of heme. The present inventors hypothesized that theSARS-CoV-2 virus leads to too much free iron in the body, by way of thevirus competing with iron for the porphyrin. Free iron in the blood isknown to trigger free radicals. Unfortunately such toxic oxidative ironwhen “disassociated” (released) may be causing numerous syndrome seen inCOVID-19, for example:

-   -   a. Damaged RBCs which may lead to tissue hypoxia. They may also        lead to debris which acts as “Pro-thrombotic material” which can        cause micro thrombi (which explain the atypical ARDS and partial        Shunt like picture observed in the COVID patients on        ventilator-supported by autopsy series). That is, it is        hypothesized by the present inventors that the hunt of        porphyrins by the virus may be associated with clotting.    -   b. The free radical iron helps to increase cytokine damage to        the lungs.

Iron supplementation might seem advantageous in treating COVID-19patients due to the virus' interference with hemogloblin. However, thepresent inventors have found this not to be true. When SFC was added to5 ALA, it was found that the iron bound to the porphyrin—there byreducing the availability of free porphyrin at the infection site. Theobservation that severe COVID-19 patients have excess blood and tissuelevels of iron can explain the failure of SFC added to 5 ALA. Thepresent inventors now recognize that treating COVID-19 patients with theiron is without substantial use as the patients have their iron strippedfrom their hemoglobin (rendering it abnormally nonfunctional). In suchcases, ventilator intubation is futile, unless one is just hoping thepatient's immune system will work its magic in time—as per few reports.While one might think iron chelators would work in accelerated healingin severe COVID patients, such drugs may be limited in use as beingunable to reach the target site.

Methylene blue is known to reduce the ferric iron in hemoglobin toferrous. The ferrous form is the form that allows oxygen carriage. Anumber of studies have surprisingly seen methemoglobemia in COVID-19patents, albeit it is not known if this is caused by treatment protocolsor the disease itself. Another well-recognized problem seen in someCOVID-19 patients is coagulopathy and hyperviscosity which may be duefibrin changes. Methylene blue is known to disturb fibrinpolymerization. It has been reported that inflammatory proteins producedduring infection in COVID-19 make platelets “hyperactive” make themaggregate faster. In a preprint dated Jun. 23, 2020 (Zaid et al.,Platelets can contain SARS-CoV-2 RNA and are hyperactivated in COVID-19,medRxiv.SARS-COV-2 RNA can be found in platelets. Such may be associatedwith the increased number of blood clots seen in COVID-19 patients.Methylene blue has been reported to inhibit arachidonic acid metabolismin human platelets in vitro (Losche et al. Methylene Blue Inhibits theArachidonic Acid Metabolism in Human Blood Platelets, Biomed. BiochimActa. 198847(10-11):S100-5103). Methylene blue has also been shown tohave antiviral properties. Thus the addition of methylene blue to a5-ALA treatment may be employed to improve clinical outcome in COVID-19cases, particularly moderate to severe cases, both due to its positiveeffect on methemoglobin, and its effect on red blood cells and plateletsto reduce hyperviscosity, along with its antiviral activity. ThusCOVID-19 patients may find particular advantage in a treatmentcomprising methylene blue alone, 5-ALA and methylene blue, or acombination of 5-ALA, methylene blue and at least one of: citric acid,cucumarin, and zinc.

In regard to all coronavirus infections, the present inventors haverecognized that viral docking needs to be controlled during the diseasestate at the purported receptor site for the virus to reduce viralreplication.

Studies on human coronaviruses OC43 and HKU1, causative agents of thecommon cold, found that both of these viruses employed sialoglycan-basedreceptors with 9-O-acetylated sialic acid (9-O—Ac-Sia) as a keycomponent. Recent studies suggest that the S1 N Terminal Domains(S1-NTD) of the spike protein knobs of SARS-CoV-2 and SARS-CoV arehiding sites for recognizing and binding glycans containing sialic acid.It is hypothesized that this recognition may be important for infectionallowing the virus to more accurately locate the ACE2 surface receptor.A recent article by Sorensen, Susrud, and Dalgeleish in QRB Discovery,after the studies reported below, suggests that ACE2 acts as the mainreceptor for SARS-CoV-2 with CLEC4M/DC-SIGN acts as a co-receptor in asimilar manner as observed for HIV and its use of CD4 as the mainreceptor and the V3 Cys-Cys loop docking on the CCR5/CXR4 co-receptors.Thus the receptor binding domain (RBD) binds to the ACE2 receptor, andthe NTD (n-terminal domain) binds to the ganglioside rich domain of thecellular plasma membrane. CLEC4M/DC-SIGN is sialic acid rich.

Curcumin is known to bind to sialic acid anchoring residues involvedwith the influenza virus (See Ou et al. Structure-activity relationshipanalysis of curcumin analogues on anti-influenza virus activity—lookingat anti-influenza virus activity of curcumin analogues—(Ou et al. FEBS280:22 (2013)). It has also been noted to reduce sialic acid levels andsialidase activity in mice with Ehrlich ascites tumors (Ozen, The TohokuJ. Experimental Medicine, September 2002: 221-7). Thus, the presentinventors hypothesized that curcumin may be may be useful in coronavirusinfections which appear to involve co-receptors, one of which isganglioside rich. In the case of COVID-19, the curcumin was thought tobe able to interfere with the ability of the virus to more efficientlydock to the ACE2 receptor.

Like 5-ALA, curcumin is a well-recognized antioxidant, also lending helpin reducing free radical damage which is a sequelae of the covoronavirusinfections. While curcumin has been shown to have many biologicalactivities, its bioavailabilty has been a stumbling block for manyyears. Numerous absorption enhancers have been employed includingpiperine, black pepper, quercetin, ascorbic acid, and phosphatidylcholine. A leap in bioavailability has occurred in respect ofnanoparticle milling and nanoparticle encapsulation.

Zinc has long been recognized as having a role in antiviral immunity(See, Read et al. Adv. Nutr 10: 696-710 (2019)) in respect of bothcoronaviruses and rhinoviruses through modulation of viral particleentry, fusion, replication, viral protein translation and furtherrelease for a number of viruses including those involved in respiratorysystem pathology. Zinc is also known to interfere with coronvirus RNApolymerase activity. At least one group has suggested that Zinc may alsobe useful in decreasing the activity of angiotensin-converting enzyme 2in COVID-19 disease (See, Skalny et al., Zinc and Respiratory TractInfections: Perspectives for COVID-19 (Review), Int. J. Mol Med. 2020Apr. 14; 46(1)”17-26). The present inventors hypothesized that if zincinterfered with angiotensin-converting enzyme 2 that it might havesynergistic effects with the curcumin in again interfering withefficient docking of the virus to the cells, improving the treatment ofCOVID-19 patients, and patients suffering from other coronavirusdiseases.

Vitamin C, or ascorbic acid, has been indicated in a number ofpublications as affecting the immune system, for example the function ofphagocytes, transformation of T lymphocytes and production ofinterferon. Vitamin C is one compound elicited as a potential target forSARS-CoV-2 by computational methods. (See, Wu et al., Analysis oftherapeutic targets for SARS-CoV-2 and discovery of potential drugs bycomputational methods, Acta Phamaceutica Sinica B. Feb. 12, 2020;10(5):776-788), It has also been suggested to increase cucumarinbioavailabilty.

On May 1, 2020 USFDA issued Emergency Use Authorization of Remdesivirfor the treatment of suspected or laboratory-confirmed COVID-19 inadults and children hospitalized with severe disease. Remdesivirinterferes with viral reproduction by being incorporated into thegrowing viral RNA strand, thereby shutting down the assembly process andhampering the virus's ability to make copies of itself. Remdesivir hasbeen reported as reducing hospitalization time by approximately 30percent. The drug has been priced in the United States for hospitalpatients with commercial insurance at $3120. Beyond Remdesivir, there isno approved treatment regimen for the Covid-19 infection as of date.However, several drug combinations, treatment regimens or methods oftreatments are being employed, none of which is approved and have onemore of the above mentioned limitations.

The inventors of the present surprisingly found that combination of 5ALA, vitamin C and curcumin can have a significant impact on COVID-19infection. The inventors anticipate such combination would to translateto other coronavirus infections, in particular those causing the commoncold. The inventors have also recognized that improvement of treatmentof coronavirus and rhinovirus infections may be had when suchcombination is used in conjunction with zinc. Furthermore, they proposeCOVID-19 treatments may be enhanced by a combination comprising at least5-ALA and methylene blue, optionally with at least one of curcumin,vitamin C, and zinc.

SUMMARY OF THE INVENTION

Accordingly, the invention herein provides a number of 5-ALA therapeuticcombinations advantageous for the treatment of coronavirus and/orrhinovirus infections. Such combinations comprise a therapeutic dose of5-aminolevulinic acid or its pharmaceutically acceptedsalts/metabolites, along with at least one of: curcumin, vitamin C, zincand methylene blue. A particular advantageous combination for thetreatment of cornonaviruses and/or rhinoviruses comprises, a therapeuticdose of 5-aminolevulinic acid, curcumin, vitamin C and Zinc. Aparticular advantageous combination for the treatment of COVID-19coronavirus comprises a therapeutic dose of 5-aminolevulinic acid,curcumin and vitamin C. A more particularly preferred embodiment for thetreatment of COVID-19 comprises a therapeutic dose of 5-aminolevulinicacid, curcumin, vitamin C and Zinc. Any of such combinations may becombined with methylene blue to form a prescription product for thetreatment of patient suffering from COVID-19, particularly moderate tosevere form. The therapeutic combinations disclosed herein are effectivein the treatment of coronavirus infections, particularly those causingthe common cold and COVID-19, and rhinoviruses, that is, in theprophylaxis, early infection and mid & late infection phases.

Such combinations may significantly reduce the time over which thepatient suffers from serious symptoms due to coronavirus and/orrhinovirus infection. Such combinations may also be used tosignificantly reduce serious complications of the infections. Thetherapeutic combinations as disclosed herein can further comprise otherantivirals and micronutrient adjuvants. Prophylaxis from coronavirusand/or rhinovirus infection may be had by consumption of the same.

The present invention also provides compositions comprising therapeuticcombination of 5-aminolevulinic acid or its pharmaceutically acceptedsalts/metabolites or the agents that shall eventually get converted toporphyrins after metabolism to raise the serum levels of porphyrinsbetween 15-45 micro mol/liter, Vitamin C, curcumin and one or morepharmaceutically acceptable excipients and also provides process forpreparing the same.

BRIEF DESCRIPTION OF THE INVENTION

One embodiment of the present invention is therapeutic combination of5-aminolevulinic acid or its pharmaceutically acceptedsalts/metabolites, Vitamin C and curcumin. In another embodiment of thepresent invention there is provided a composition comprising5-aminolevulinic acid or its pharmaceutically acceptedsalts/metabolites, Vitamin C and curcumin and one or morepharmaceutically acceptable excipients.

In an another embodiment of the present invention provides therapeuticcombination of 5-aminolevulinic acid or its pharmaceutically acceptedsalts/metabolites, vitamin C and curcumin further comprising otherantivirals and/or micronutrient adjuvants. In an another embodiment ofthe present invention there is provided a process for preparing acomposition comprising 5-aminolevulinic acid or its pharmaceuticallyaccepted salts/metabolites, vitamin C, curcumin and zinc and one or morepharmaceutically acceptable excipients.

In another embodiment of the present invention provides methods oftreating coronavirus infections, including Covid-19. The method oftreatment comprises the step(s) of administering a therapeuticcombination of 5-aminolevulinic acid or its pharmaceutically acceptedsalts/metabolites, vitamin C and curcumin. The therapeutic combinationcan be administered as prophylactic treatment as well as to a patient inneed thereof who is having early infection or mid and late infectionphases. The therapeutic combination as disclosed herein advantageouslyachieves a therapeutic synergy in treating the Covid-19 in thepatient/subject.

5 ALA is administered preferably as a solid as 5 ALA hydrochloride or 5ALA phosphate although oil can be. The 5 ALA is administered in dosageof 1-1600 mg, more preferably 100 mg-1600 mg, yet more preferably 200mg-1600 mg, or 300 mg-1600 mg in in single or divided doses of twicedaily or thrice daily. In a preferred amount, ALA dosage is set to allowfor serum levels of porphyrins between 15-45 micro mol/liter to bereached The dosage of 5-ALA is given based on weight of thepatient/severity of infection.

Vitamin C is administrated in dosage of 1-1000 mg, more preferably 80mg-1000 mg, and yet more preferably 500 mg-1000 mg in single or divideddoses of twice daily or thrice daily. The dosage of Vitamin C is givenbased on weight of the patient/severity of infection.

Curcumin is administered in dosage of 1-1000 mg, more preferably 50mg-1000 mg, and yet more preferably 100 mg-1000 mg in single or divideddoses of twice daily or thrice daily. The dosage of Curcumin is givenbased on weight of the patient/severity of infection. Curcumin maypreferably be administered in micronized or nanoform of curcumin forfaster and more complete absorption.

Zinc is administered in a dosage of 5 mg-150 mg a day. More preferably5-100 mg a day in single or divided doses. Zinc may in one embodiment beadministered as zinc gluconate or zinc bis-glycinate.

In the treatment of COVID-19, methylene blue may be optionally added tosuch combinations in a dose of 1 mg/kg i.v. or orally at 1-30 mg/kg,more preferably 2.5-25 mg/kg, or 1-4500 mg, more preferably 50 mg-250mg, in single or divided doses of twice daily or thrice daily. Methyleneblue is available as an injectable and as an oral tablet. No suppositoryof such drug is known. It is herein suggested that treatment withmethylene blue can be by way of suppository, allowing for treatment thatallows the drug to be effectively absorbed without the need forintravenous or per os administration.

Administration of the compounds and compositions described herein can beeffected by any method that enables delivery of the compounds to thesite of action. These methods include, though are not limited todelivery via enteral routes (including oral, gastric or duodenal feedingtube, rectal suppository and rectal enema), parenteral routes (injectionor infusion, including intraarterial, intracardiac, intradermal,intraduodenal, intramedullary, intramuscular, intraosseous,intraperitoneal, intrathecal, intravascular, intravenous, intravitreal,epidural and subcutaneous), inhalational, transdermal, transmucosal,sublingual, buccal and topical (including epicutaneous, dermal, enema,eye drops, ear drops, intranasal, vaginal) administration, although themost suitable route may depend upon for example the condition anddisorder of the recipient. The compositions may be made intosuppositories, lozenges, sachets. A novel methylene blue plus 5-ALAcombination made be employed in a suppository or lozenge.

Antivirals may find particular synergistic effect with the describedcompositions in the treatment of COVID-19 and may be selected from atleast one of: abacavir, lamivudine, zidovudine, didanosine, nevirapine,stavudine, lopinavir, ritonavir, tenofovir, emtricitabine, dolutegravir,raltegravir, cabotegravir, cobicistat, rilpivirine, favipiravir,remdesivir, efavirenz, atazanavir, elvitegravir, etravirine, maravirocand its pharmaceutically acceptable salts or esters or prodrugs andcombinations thereof. Particularly useful antivirals to provide synergicantiviral activity of such combinations include remdesivir,hydroxychloroquine, and chloroquine.

Anti-inflammatories may also find synergistic use in treating severeCOVID-19 patients selected from at least one of carprofen, clecoxib,baricitinib, and dexamethasone and their pharmaceutically acceptablesalts or esters or prodrugs and combinations thereof.

If venous or arterial thrombosis or clinical signs of clotting areshown, anticoagulants in severe COVID-19 may also be employed with suchcompositions such as enaxoaprin, warfarin, or heparin.

Micronutrient adjuvants as described herein are selected from the groupcomprising of micro minerals, antioxidants (such as Vitamin E,beta-carotene, selenium, coenzyme Q10), choline and vitamins. Microminerals are selected from the, uric acid group consisting of cobalt,chromium, copper, iodine, potassium, calcium, manganese, selenium, zinc,and molybdenum and its pharmaceutically acceptable salts andcombinations thereof.

The therapeutic combination according to the present invention isadministrated for at least 14 days, specifically at least 10 days, morespecifically for at least 7 days, and may have application over 2-7days. Specifically the treatment period is selected depend on severityof virus infection.

The combination according to the present invention may be in the form ofkit comprising 5-aminolevulinic acid or its pharmaceutically acceptedsalts/metabolites, Vitamin C and Curcumin or tablets or capsules orsuspension or solution or injection dosage form.

The combination according to the present invention may be in the form ofco-packing comprising 5-aminolevulinic acid or its pharmaceuticallyaccepted salts/metabolites, Vitamin C and Curcumin or tablets orcapsules form.

The tablet dosage form according to the present invention may be animmediate release or extended release form. Further the tablet dosageform may be monolayer or bi-layer or tri-layer tablet or layered tabletscontaining active drug in different coating layers. In a preferredembodiment the tablet is an orally disintegrable tablet.

In an embodiment of the present invention the dosage form may be pelletsof 5-aminolevulinic acid or its pharmaceutically acceptedsalts/metabolites, Vitamin C, and curcumin filled in capsules orcompressed into tablets.

The therapeutic combinations according to the present invention maycomprise one or more pharmaceutically acceptable excipients.

One or more pharmaceutically acceptable excipients are advantageouslyselected from diluents, binders, disintegrants, lubricants, glidants,sweetening agents, flavoring agents and colorants and combinationsthereof.

Diluents are inactive ingredients that are added to tablets and capsulesin addition to the active drug. A good diluent must be inert, compatiblewith the other components of the composition, non-hygroscopic,relatively cheap, compatible, and preferably tasteless or pleasanttasting. Suitable diluents according to the present invention areselected from mannitol, micro crystalline cellulose, lactose, sucrose,glucose, sorbitol, starch and its derivatives, dibasic calcium phosphateand combinations thereof.

Binders are agents added to tablet/capsule/granule composition forbinding with other substances to form granules and are selected from thegroup consisting of povidone, starch, potato starch, wheat starch, cornstarch, hydroxypropyl methylcellulose, hydroxypropyl cellulose,hydroxyethyl cellulose, gelatin and combinations thereof.

Disintegrants are agents added to tablet/capsule composition to promotethe breakup of the granules/tablet into the small fragments in anaqueous environment thereby increasing the available surface area andpromoting a more rapid release of the drug substance. Suitabledisintegrants according to the present invention are selected fromCrospovidone, croscarmellose sodium, croscarmellose calcium, starch andits derivatives, sodium starch glycolate, polacrilin sodium, lowsubstituted hydroxypropyl cellulose, silicified microcrystallinecellulose and combinations thereof.

Lubricants are agents which prevent ingredients from clumping togetherand from sticking to the tablet punches or capsule filling machine.Lubricants also ensure that tablet formation and ejection can occur withlow friction between the solid and die wall. Suitable lubricantsaccording to the present invention are selected from calcium stearate,magnesium stearate, stearic acid, and talc and combinations thereof.

Glidants are agents these are used to promote powder flow by reducinginter particle friction and cohesion. Suitable glidants according to thepresent invention are selected from colloidal silicon dioxide, talc andstarch.

Sweetening agents are substances that sweeten medications, food,beverages etc., and suitable sweeteners according to the presentinvention are selected from aspartame, sucralose, xylitol, sweefil,sweegel, saccharine, sorbitol, maltitol, and combinations thereof.

Flavoring agents are substances added to medicines and foods to improvethe quality of taste. Suitable flavoring agents according to the presentinvention may be selected from vanilla flavor, forest fruit flavor,fruit essences, peppermint oil, spear mint oil, clove oil, orange oil,anise oil and combinations thereof.

Colorants are agents which gives a special character or distinguishingquality to the pharmaceutical dosage forms. Coloring may be required toincrease the aesthetic appearance or identification of a particularcomposition. Suitable colorants according to the present invention maybe selected from indigo carmine lake, iron oxide yellow and iron oxidered and combinations thereof.

The compositions are prepared by techniques known by the skilled personin the art like direct compression or wet granulation or drygranulation. The compositions may be in form of powder and may be filledin capsules or sachets or may be compressed into tablets of immediaterelease or orally disintegrating or modified release.

Direct compression technique generally involves blending all ingredientsin a blender for suitable time till to achieve blend uniformity andcompressing into tablets of suitable size and shape.

Wet granulation technique generally involves utilization of solvents forpreparation of granules. This process generally has the steps of mixingactive ingredient with diluent, optionally disintegrant, granulatingthis mixture either by aqueous or non-aqueous granulation, drying thegranulate, optionality sieving dried granules and blending driedgranules with optionally further diluent, disintegrant, optionallysweetening agent, optionally flavoring agent, optionally colorant andlubricated with lubricant. Suitable solvents used according to thepresent invention for preparation of wet granulation are selected fromwater, isopropyl alcohol, methylene chloride and combinations thereof.

Dry granulation is another technique which doesn't use any solvents forpreparation of granules. This process generally has the steps of mixingactive ingredient with diluent, optionally disintegrant, optionallylubricant, optionally glidant, slugging and de-slugging and blendingwith optionally diluent, optionally disintegrant, optionally lubricant,optionally glidant, optionally sweetening agent, optionally flavoringagent, optionally colorant.

Release modifying agents are used to modify the drug release from thedosage form. Suitable release modifying agents may be selected fromhydroxypropyl methylcellulose, hydroxyl propyl cellulose, ethylcellulose, methyl cellulose, carboxy propyl methyl cellulose,polyethylene oxide, xanthan gum, guar gum, Methacrylates, polyvinylpyrrolidone, polyvinyl chloride, polypropylene and gelatin.

EXAMPLES

The present invention is further defined in the following examples. Itshould be understood that these examples, while indicating preferredembodiments of the invention are given by way of illustration only. Fromthe above discussion and these examples, one skilled in the art canascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various uses andcondition.

The invention is illustrated by the following non limiting examples:

Example 1 Tablet Embodiment 1

Ingredient mg/tablet 5-aminolevulinic acid or its salt 300 mg Curcumin100 mg Vitamin C  40 mg Microcrystalline cellulose 240 mg Starch corn 60 mg Croscarmellose sodium  20 mg Magnesium stearate  10 mg Total 770mg Film coating  15 mg Total tablet weight 785 mg

Example 2 Tablet Embodiment 2

Ingredient mg/tablet 5-aminolevulinic acid or its salt 300 mg Curcumin100 mg Vitamin C  40 mg Zinc Gluconate  50 mg Microcrystalline cellulose210 mg Starch corn  40 mg Croscarmellose sodium  20 mg Magnesiumstearate  10 mg Total 770 mg Film coating  15 mg Total tablet weight 785mgManufacturing Process:

Sift all the ingredients, blend 5-aminolevulinic acid or its salt,Curcumin, Vitamin C, with or without Zinc. Microcrystalline cellulose,Starch corn and Croscarmellose sodium in a blender for 20 minutes andthe blend is lubricated by adding magnesium stearate to the blender andblend for 5 minutes. Finally compress the blend into tablets and filmcoated the compressed tablets.

Example 3 Multilayer Tablet Embodiment 3

Ingredient mg/tablet Layer 1 5-aminolevulinic acid or its salt 300 mgMicrocrystalline cellulose 150 mg Povidone  10 mg Sodium starchglycolate  10 mg Purifier water q.s Magnesium stearate  5 mg Layer 1tablet weight 475 mg Layer 2 Curcumin 100 mg Starch corn  60 mg Sodiumstarch glycolate  10 mg Magnesium stearate  5 mg Layer 2 tablet weight175 mg Layer 3 Vitamin C  40 mg Microcrystalline cellulose 150 mg Sodiumstarch glycolate  10 mg Magnesium stearate  5 mg Layer 3 tablet weight205 mg Total 855 mg Film coating  25 mg Total tablet weight 880 mgManufacturing Process:Layer 1:

Sift all the ingredients, blend 5-aminolevulinic acid or its salt,Microcrystalline cellulose, Sodium starch glycolate for 10 minutes;dissolve povidone in purified water and make binder solution; add slowlybinder solution to the blend to form granules; dried the granules;loaded the granules into blender and add magnesium stearate to the blendand blend for 5 minutes.

Layer 2:

Sift all the ingredients, blend curcumin, Starch corn, and Sodium starchglycolate in a blender for 15 minutes and the blend is lubricated byadding magnesium stearate to the blender and blend for 5 minutes.

Layer 3:

Sift all the ingredients, blend Vitamin C, Microcrystalline cellulose,Sodium starch glycolate for 10 minutes; and the blend is lubricated byadding magnesium stearate to the blender and blend for 5 minutes.

Compress: Compress Layer 1, Layer 2 and Layer 3 blends into trilayertablets.

Coating: Trilayer tablets coated with film coating.

Example 4 Sachet Embodiment

Ingredient mg/tablet 5-aminolevulinic acid or its salt 300 mg Curcumin100 mg Vitamin C  40 mg Mannitol 200 mg Sorbitol  50 mg Fruit flavor  10mg Total 700 mgManufacturing Process:

Sift all the ingredients, blend 5-aminolevulinic acid or its salt,Curcumin, Vitamin C, Mannitol, Sorbitol and Fruit flavor in a blenderfor 20 minutes and the blend is filled in sachets.

Example 5 Lozenge Embodiment

Ingredient mg/tablet 5-aminolevulinic acid or its salt   300 mg Curcumin  100 mg Zinc Gluconate  13.3 mg Vitamin C   40 mg Acesulfame Potassium182.7 mg Glycine   50 mg Isomalt    7 mg Fruit flavor    7 mg Total  700 mg

Example 6

15 SARS-CoV-2 hospitalized patients consume 200 mg 2-3 times daily 5-ALAphosphate, over 5-14 days, along with cucumarin nano 100 mg for 7-14days, and vitamin C 80 mg-1000 mg over 7-14 days. Such treated cohort isotherwise treated with standard care for COVID-19 patients. The controlcohort comprises 20 hospitalized patients receiving the same standardcare but without consumption of 5-ALA, nano-cucumarin, or Vitamin C. Twopatients in the control cohort develop the need for ICU admission, whilenone of the treated cohort advance to ICU. Total stay time in thehospital is reduced from a mean of 9.40±1.029 days to 7.07±0.67. Meanerythrocyte sedimentation rate (“ESR”), which is inverse to bloodviscosity, is seen to be reduced from 23.35±8.419 in control to16.33±3.90 in treatment group. Better five day viral clearance by nasalswab is seen in the treatment cohort (60%) versus control control (35%).Less disseminated intravascular coagulation is noted in the treatmentcohort.

Example 7

Persons inflicted with a coronavirus infections are given at treatmentof a daily dose of 300 mg-1600 mg 5-ALA phosphate, Vitamin C 80 mg-1000mg, cucumarin nano 100-1000 mg, and zinc in a total of 5 mg-100 mg aszinc gluconate and/or zinc bis-glycinate. Such are provided in a singleor divided doses of twice daily or thrice daily.

Example 8

Persons seeking prophylaxis against coronavirus infections are given attreatment of a daily dose of 300 mg-1600 mg 5-ALA phosphate, Vitamin C80 mg-1000 mg, 100-1000 mg cucumarin nano, and zinc in a total of 5mg-100 mg as zinc gluconate and/or zinc bis-glycinate. Such are providedin a single or divided doses of twice daily or thrice daily.

Example 9

Persons seeking prophylaxis against, and/or amelioration of coronavirusinfections, are given at treatment of a daily dose of 300 mg-1600 mg5-ALA phosphate, Vitamin C 80 mg-1000 mg, 100-1000 mg cucumarin nano,and zinc in a total of 5 mg-100 mg as zinc gluconate and/or zincbis-glycinate. Such are provided in a single or divided doses of twicedaily or thrice daily.

Example 10

Persons suffering from moderate or severe COVID-19 are given treatmentwith a dose of 300 mg-1600 mg 5-ALA phosphate with at least one ofVitamin C 80 mg-1000 mg, 100-1000 mg cucumarin nano, zinc in a total of5 mg-100 mg as zinc gluconate and/or zinc bis-glycinate, and methyleneblue in a dose of 50 mg-250 mg. Such are provided in a single or divideddoses of twice daily or thrice daily.

Example 1 Tablet Embodiment 4

Ingredient mg/tablet 5-aminolevulinic acid or its salt 300 mg Curcumin100 mg Vitamin C  40 mg Zinc Gluconate  50 mg Metthlene Blue  50 mgMicrocrystalline cellulose 160 mg Starch corn  40 mg Croscarmellosesodium  20 mg Magnesium stearate  10 mg Total 770 mg

Example 12 Suppository Embodiment

Persons suffering from moderate or severe COVID-19 are given treatmentwith a suppository containing:

Ingredient mg/tablet 5-aminolevulinic acid or its salt  300 mg Methyleneblue  100 mg Theobroma Oil 1600 mg

The suppositories are molded so to have one end tapered.

The invention claimed is:
 1. A method for amelioriation of a viralinfection comprising administering to a patient in need of treatment atherapeutically effective amount of 5-aminolevulinic acid, orpharmaceutically acceptable salt thereof.
 2. The method of claim 1wherein the viral infection is an infection by SARS-CoV-2.
 3. The methodof claim 1 wherein the viral infection is associated with the commoncold.
 4. The method of claim 1 wherein the therapeutically effectiveamount of 5-aminolevulinic acid is 100 mg-1600 mg provided in a singleor divided doses of twice daily or thrice daily.
 5. The method of claim1 wherein the therapeutically effective amount of 5-aminolevulinic acidis 200 mg-1600 mg provided in a single or divided doses of twice dailyor thrice daily.
 6. The method of claim 1 wherein the therapeuticallyeffective amount of 5-aminolevulinic acid is 300 mg-1600 mg provided ina single or divided doses of twice daily or thrice daily.
 7. Apharmaceutical composition comprising 5-aminolevulinic acid orpharmaceutically acceptable salt thereof, and a non-iron micronutrient,each present in therapeutically effective amounts, in an admixture withpharmaceutically acceptable excipient.
 8. The composition of claim 7wherein the therapeutically effective amount of 5 aminolevulinic acid is100 mg-1600 mg provided in a single or divided doses of twice daily orthrice daily.
 9. The composition of claim 7 wherein the therapeuticallyeffective amount of 5 aminolevulinic acid is 200 mg-1600 mg provided ina single or divided doses of twice daily or thrice daily.
 10. Thecomposition of claim 7 wherein the therapeutically effective amount of5-aminolevulinic acid is 300 mg-1600 mg provided in a single or divideddoses of twice daily or thrice daily.